Final analysis of the phase 3 randomized clinical trial comparing HD201 vs. referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting.

BACKGROUND: The TROIKA trial established that HD201 and trastuzumab were equivalent in terms of primary endpoints (total pathological complete response) following neoadjuvant treatment. The objective of the present analysis was to compare survival outcomes and final safety. METHODS: In the TROIKA trial, patients with ERBB2-positive early breast cancer were randomized and treated with either HD201 or the referent trastuzumab. Eligible patients received 8 cycles of either HD201 or referent trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in combination with 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) in the neoadjuvant setting. The patients then underwent surgery followed by 10 cycles of adjuvant HD201 or referent trastuzumab according to their initial randomization to complete one year of trastuzumab-directed therapy. Event-free and overall survival rates were calculated using Kaplan-Meier analysis. The hazard ratio for event-free survival was estimated by Cox proportional hazards regression. RESULTS: The final analysis was performed after all patients completed the study at a median follow-up of 37.7 months (Q1-Q3, 37.3-38.1 months). A total of 502 randomized patients received either HD201 or the referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. In this population, the 3-year event-free survival rates were 85.6% (95% CI: 80.28-89.52) and 84.9% (95% CI: 79.54-88.88) in the HD201 and referent trastuzumab groups, respectively (log rank p = 0.938) (HR 1.02, 95% CI: 0.63-1.63; p = 0.945). The 3-year overall survival rates were comparable between the HD201 (95.6%; 95% CI: 91.90-97.59) and referent trastuzumab treatment groups (96.0%, 95% CI: 92.45-97.90) (log rank p = 0.606). During the posttreatment follow-up period, adverse events were reported for 64 (27.4%) and 72 (29.8%) patients in the HD201 and the reference trastuzumab groups, respectively. Serious adverse events were rare and none of which were related to the study treatment. CONCLUSIONS: This final analysis of the TROIKA trial further confirms the comparable efficacy and safety of HD201 and trastuzumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03013504.

Efficacy of HD201 vs Referent Trastuzumab in Patients With ERBB2-Positive Breast Cancer Treated in the Neoadjuvant Setting: A Multicenter Phase 3 Randomized Clinical Trial.

Importance: The drug HD201 is a biosimilar candidate for breast cancer treatment as the reference trastuzumab. Objective: To compare the efficacy of HD201 with referent trastuzumab. Design, Setting, and Participants: This randomized clinical trial (TROIKA) included 502 women with ERBB2-positive early breast cancer treated with either HD201 or referent trastuzumab. It was conducted across 70 centers in 12 countries, including Western and Eastern Europe and Asian countries. Randomization was stratified by tumor hormone receptor status, clinical stage, and geographic region of recruitment. This analysis was conducted on February 12, 2021, after the completion of the adjuvant phase at a median of 31 months (IQR, 28-33 months) of follow-up. Interventions: Patients with ERBB2-positive early breast cancer were randomly assigned to receive HD201 or referent trastuzumab in the neoadjuvant setting for 8 cycles, concurrently with 4 cycles of docetaxel, which was followed by 4 cycles of epirubicin and cyclophosphamide. Patients then underwent surgery, which was followed by treatment with 10 cycles of adjuvant HD201 or referent trastuzumab. Main Outcome and Measures: The primary end point was the total pathological complete response (tpCR) assessed after neoadjuvant treatment. Equivalence was concluded if the 95% CI of the absolute difference in tpCR between arms in the per-protocol set was within the margin of more or less than 15%. Other objectives included the breast pathological complete response, overall response, event-free and overall survival, safety, pharmacokinetics, and immunogenicity. Results: A total of 502 female patients (mean [range] age, 53 [26-82] years) were randomized to receive either HD201 or referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. The baseline characteristics were well balanced between the 2 arms; 195 tumors (38.8%) were hormone receptor-negative , and 213 patients (42.4%) had clinical stage III disease. The tpCR rates were 45% and 48.7% for HD201 and referent trastuzumab, respectively. The difference between the 2 groups was not significant at -3.8% (95% CI, -12.8% to 5.4%) and fell within the predefined equivalence margins. The ratio of the tpCR rates between the 2 arms was 0.92 (95% CI, 0.76 to 1.12). A total of 433 patients (86.1%) presented with 2232 treatment-emergent adverse events of special interest for trastuzumab during the entire treatment period, with 220 (88.0%) and 213 (84.5%) patients in the HD201 and referent trastuzumab groups, respectively. Conclusions and Relevance: The results of this randomized clinical trial found that HD201 demonstrated equivalence to referent trastuzumab in terms of efficacy for the end point of tpCR, with a similar safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT03013504.

TROIKA-1: A double-blind, randomized, parallel group, study aimed to demonstrate the equivalent pharmacokinetic profile of HD201, a potential biosimilar candidate to trastuzumab, versus EU-Herceptin® and US-Herceptin® in healthy male subjects.

Prestige Biopharma Ltd (Singapore) has developed HD201, a proposed biosimilar to reference product trastuzumab. As a part of the stepwise approach to ensure comparability between the biosimilar candidate and the reference medicinal product, a phase I study in healthy subjects was conducted to demonstrate the pharmacokinetic (PK) equivalence (NCT03776240). The primary objective of the study was to demonstrate (PK) equivalence of HD201, EU-Herceptin® , and US-Herceptin® given at 6 mg/kg as a 90-min i.v. infusion to healthy male subjects. A pairwise comparisons based on the primary endpoint AUC0-inf and secondary PK endpoints, AUC0-last and Cmax were undertaken. PK equivalence was to be concluded if the 90% confidence interval (CI) for the ratio of geometric means for each criterion were within the equivalence margin of 80% to 125%. Secondary objectives included assessment of other PK parameters, safety, tolerability, and immunogenicity in the three arms. A total of 105 healthy male subjects (35/treatment) were randomized in this study. The 90% CI for the ratios of AUC0-inf , Cmax and AUC0-last , were within 80%-125% for the comparisons of HD201 to EU-Herceptin® or US-Herceptin® and EU-Herceptin® to US-Herceptin® . The frequency of subjects with TEAEs of special interest was slightly lower in the HD201 group (20.0%) compared to the other treatment groups (EU-Herceptin® : 34.3%; US-Herceptin® : 31.4%). Only 1 subject (EU-Herceptin® group) developed anti-drug antibodies prior to dosing. Overall, HD201 demonstrates PK similarity to both EU-Herceptin® and US-Herceptin® . The three study drugs also demonstrated similar safety profiles.

A randomized phase I study comparing the pharmacokinetics of a bevacizumab (HD204) biosimilar to European Union- and United States of America-sourced bevacizumab.

PURPOSE: This first-in-human study was designed to evaluate the pharmacokinetic (PK) equivalence between HD204 and the European Union (EU)-sourced bevacizumab, between HD204 and the United States of America (US)-sourced bevacizumab, and between EU-sourced and US-sourced bevacizumab (NCT03390673). METHODS: In this randomized, double-blind, 3-way parallel group, single-dose comparative PK study, healthy male subjects were randomized to receive a single 1 mg/kg intravenous dose of HD204, EU-sourced bevacizumab or US-sourced bevacizumab. PK parameters were calculated using non-compartmental methods. PK equivalence was determined using the pre-defined equivalence margin of 0.8-1.25 in terms of AUC(0-∞) for the pairwise comparisons. FINDINGS: Baseline demographics for the 119 randomized subjects were similar across the three groups. The 90% CIs for the ratio of the geometric means of HD204 to US-sourced bevacizumab, HD204 to EU-sourced bevacizumab, and EU-sourced to US-sourced bevacizumab were all within the interval of 80% to 125% for AUC0-inf, thus demonstrating equivalency in the PK properties for all three treatment groups. Similarly, the ratio of the geometric means for AUC0-last and Cmax were all within the 80% and 125% margins, supporting the robustness of the primary findings. All other PK parameters, including the half-life (t1/2) clearance (CL), volume of distribution (Vd) and time of maximum concentration (tmax), were comparable. There was no difference between the 3 treatment arms in terms of vital signs, laboratory tests and adverse events. None of the subjects treated with HD204 had positive ADA results. IMPLICATIONS: HD204 demonstrates equivalent pharmacokinetic profiles compared to those of both US-sourced and EU-sourced bevacizumab. (NCT03390673).

Voriconazole treatment of invasive aspergillosis: real-world versus health-economic model results.

OBJECTIVE: The objective of this study was to assess, in a real-world setting, the predictive validity (in terms of clinical outcome and treatment cost) of the voriconazole arm of a health-economic model applied in the Belgian reimbursement submission for use of voriconazole in the treatment of invasive aspergillosis. METHODS: A non-interventional study was designed to prospectively collect clinical response and direct costs data related to the treatment of invasive aspergillosis with voriconazole (oral, intravenous) in real-world practice. The outcomes of this study were compared with the inputs and outputs of the health-economic model. For the analysis, unit costs of 2002 from the public payer's perspective, as used in the model, were applied. RESULTS: Data from 116 patients with invasive aspergillosis starting treatment with voriconazole were collected. At 12 weeks, there were similar rates of satisfactory clinical response for the observational study and the model, the latter based on the results of a clinical study (50% vs 53%, respectively). Overall mortality rates at 84 days were 42% in the observational study and 29% in the model. Average total healthcare cost associated with voriconazole treatment was lower in the observational study compared with the model for all patients. When the cost for all hospitalization days from the start until the end of the fungal infection was included in the analysis, the average total cost was euro19,674. When the cost for only those hospitalization days solely related to the fungal infection was included in the analysis, the average total cost was euro12,376. These costs are below the cost predicted by the model of euro21,298. CONCLUSIONS: This analysis demonstrates that the results provided in the voriconazole arm of the health-economic model were valid estimates with regard to real-world outcomes but with a slightly better survival rate and higher costs than in real life.

Non-interventional study comparing treatment satisfaction in patients treated with antihistamines.

BACKGROUND AND OBJECTIVE: Allergic rhinitis and urticaria are common allergic disorders that may affect approximately 15% of people at some time in their lives. Antihistamines are the most widely used therapeutic interventions for these disorders but the newer generation agents have differing pharmacokinetic characteristics that may result in different patient satisfaction and preferences. The objective of this study was to investigate patients' and physicians' satisfaction with their current antihistamine treatment for allergic disease. METHODS: In an observational study, physicians in nine European countries completed questionnaires evaluating 7,274 patients treated with an oral antihistamine. The satisfaction of patients and physicians with the efficacy and tolerability of treatment was rated on a visual analogue scale. In addition, the proportion of patients satisfied with treatment (overall satisfaction) and willing to continue treatment with the same antihistamine were assessed. Safety and tolerability data were also gathered. RESULTS: The results of this study indicate that modern antihistamines are generally considered effective and well tolerated by patients. In general, levocetirizine scored significantly higher in terms of perception of efficacy, tolerability and overall satisfaction. In terms of tolerability, three-quarters of patients were 'very satisfied' and a further fifth were moderately satisfied with levocetirizine and almost all (95%) were happy to continue treatment. Overall, the most commonly reported adverse event in this study was somnolence, a well known effect of antihistamines. The rate of somnolence in the levocetirizine group (3.8%) was similar to that for fexofenadine (both doses) and desloratadine, two products which are considered to be nonsedating antihistamines, and significantly less than half the rate for cetirizine. CONCLUSION: Levocetirizine is considered an effective and well tolerated option for treating allergic disease by patients and physicians alike, particularly when the best available effectiveness and tolerability are required.

Neonatal data on a cohort of 2889 infants born after ICSI (1991-1999) and of 2995 infants born after IVF (1983-1999).

BACKGROUND: To evaluate the safety of ICSI, this study compared data of IVF and ICSI children by collecting data on neonatal outcome and congenital malformations during pregnancy and at birth. METHODS: The follow-up study included agreement to genetic counselling and eventual prenatal diagnosis, followed by a physical examination of the children after 2 months, after 1 year and after 2 years. 2840 ICSI children (1991-1999) and 2955 IVF children (1983-1999) were liveborn after replacement of fresh embryos. ICSI was carried out using ejaculated, epididymal or testicular sperm. RESULTS: In the two cohorts, similar rates of multiple pregnancies were observed. ICSI and IVF maternal characteristics were comparable for medication taken during pregnancy, pregnancy duration and maternal educational level, whereas maternal age was higher in ICSI and a higher percentage of first pregnancies and first children born was observed in the ICSI mothers. Birthweight, number of neonatal complications, low birthweight, stillbirth rate and perinatal death rate were compared between the ICSI and the IVF groups and were similar for ICSI and IVF. Prematurity was slightly higher in the ICSI children (31.8%) than in the IVF children (29.3%). Very low birthweight was higher in the IVF pregnancies (5.7%) compared with ICSI pregnancies (4.4%). Major malformations (defined as those causing functional impairment or requiring surgical correction), were observed at birth in 3.4% of the ICSI liveborn children and in 3.8% of the IVF children (P = 0.538). Malformation rate in ICSI was not related to sperm origin or sperm quality. The number of stillbirths (born > or =20 weeks of pregnancy) was 1.69% in the ICSI group and 1.31% in the IVF group. Total malformation rate taking into account major malformations in stillborns, in terminations and in liveborns was 4.2% in ICSI and 4.6% in IVF (P = 0.482). CONCLUSIONS: The comparison of ICSI and IVF children taking part in an identical follow-up study did not show any increased risk of major malformations and neonatal complications in the ICSI group.